Anticancer gold complexes: Controlled activation, precision targeting and beyond

Gold-based drugs possess a long history of clinical treatment of rheumatoid arthritis with a favorable safety profile. Their unique mechanism of action involving redox regulation holds promise for overcoming the common resistance and toxicity issues associated with platinum-based drugs. However, the further development of gold drugs still faces several key challenges, primarily including off-target binding, immunosuppressive toxicity, and insufficient selectivity for thioredoxin reductase (TrxR) isoforms. This review summarizes the unique strategies from the group of Zou to address these issues, involving stimulus-responsive gold prodrugs to overcome albumin-mediated off-target binding; a subcellular photocatalysis strategy for selective inhibition of TrxR1; and a dynamic ligand exchange strategy enabling the therapeutic repurposing of the approved drug auranofin at clinically relevant doses for anticancer treatment. Furthermore, we have designed and developed metal-based drugs with immunogenic cell death (ICD) activity and conducted an in-depth exploration of their targets and related mechanisms. Future perspectives highlight critical research pathways required for realizing the full therapeutic potential of these metal complexes in actual clinical settings.